The objective of this proposed project is to examine (i) the cause for the reduced basal glucose metabolism in the skeletal muscle and its resistance to insulin stimulation and (ii) the correlation between altered insulin stimulation of glucose metabolism and insulin binding and their role in the development of insulin resistance and hyperglycemia in the genetically obese-hyperglycemic mice (db/db/ and ob/ob). The perfused mouse hindquarter preparation will be used to measure glucose utilization, gluco se transport, glucose phosphorylation, insulin binding, amino acid uptake and release, protein synthesis and calcium mobilization. These parameters will be examined in animals age 4-6 weeks (a normal glycemic, hyperinsulinemic and mildly obese period) and 8-12 weeks (a hyperglycemic, hyperinsulinemic and overtly obese stage). Glucose metabolism insulin sensitivity and insulin binding in the perfused hindquarters of mice fed, fasted, treated with streptozotocin or adrenalectomized, conditions which either improve their insulin sensitivity, improve basal glucose metabolism, lower blood glucose and/or blood insulin levels, will be correlated. The role of altered amino acid uptake, release and protein turnover and their responsiveness to insulin, in contributing to the development of hyperglycemia will be examined.